1. The Interferon Signaling Antagonist Function of Yellow Fever Virus NS5 Protein Is Activated by Type I Interferon
- Author
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Laurent-Rolle, Maudry, Morrison, Juliet, Rajsbaum, Ricardo, Macleod, Jesica M Levingston, Pisanelli, Giuseppe, Pham, Alissa, Ayllon, Juan, Miorin, Lisa, Martínez-Romero, Carles, tenOever, Benjamin R, and García-Sastre, Adolfo
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Emerging Infectious Diseases ,Infectious Diseases ,Biodefense ,Vaccine Related ,Prevention ,Infection ,Amino Acid Motifs ,Animals ,Cell Line ,GTP-Binding Proteins ,Host-Pathogen Interactions ,Humans ,Interferon-beta ,Phosphorylation ,Protein Binding ,STAT1 Transcription Factor ,STAT2 Transcription Factor ,Signal Transduction ,Viral Nonstructural Proteins ,Yellow Fever ,Yellow fever virus ,Microbiology ,Medical Microbiology ,Immunology ,Biochemistry and cell biology ,Medical microbiology - Abstract
To successfully establish infection, flaviviruses have to overcome the antiviral state induced by type I interferon (IFN-I). The nonstructural NS5 proteins of several flaviviruses antagonize IFN-I signaling. Here we show that yellow fever virus (YFV) inhibits IFN-I signaling through a unique mechanism that involves binding of YFV NS5 to the IFN-activated transcription factor STAT2 only in cells that have been stimulated with IFN-I. This NS5-STAT2 interaction requires IFN-I-induced tyrosine phosphorylation of STAT1 and the K63-linked polyubiquitination at a lysine in the N-terminal region of YFV NS5. We identified TRIM23 as the E3 ligase that interacts with and polyubiquitinates YFV NS5 to promote its binding to STAT2 and trigger IFN-I signaling inhibition. Our results demonstrate the importance of YFV NS5 in overcoming the antiviral action of IFN-I and offer a unique example of a viral protein that is activated by the same host pathway that it inhibits.
- Published
- 2014